ES2240335T3 - PREPARATION PROCEDURE FOR ISOMEROS DE SALBUTAMOL. - Google Patents

Abstract

A process for making optically Optically pure (R) and (S) salbutamol comprises obtaining the (R) or (S) isomer of either salbutamol or a salbutamol precursor in substantially optically pure form is obtained by resolving a racemic or optically impure mixture of enantiomers of salbutamol or of said a salbutamol precursor with either (L) or (D) tartaric acid, and where necessary converting said isomer of said precursor into either (R) or (S) salbutamol respectively; then optionally converting said optically pure (R) and/or (S) salbutamol into a pharmaceutically acceptable salt.

Description

Preparation process for isomers of Salbutamol

The invention relates to an improved method of optically obtain the (R) salbutamol also known as (R) Albuterol The chemical name of salbutamol is α - [[(1,1-dimethyl-ethyl) amino] methyl] -4-hydroxy-1,3-benzenedimethanol.

It is known that for certain conditions that need medical treatment such as asthma, the isomer (R) of salbutamol (which is levógiro, indicated by (-) or l) is much more therapeutically potent than the dextrogiro (S) isomer. A method of preparing the (R) and (S) isomers of salbutamol in optically pure form is that described in US Patent 5,545,745. In this method, one or another of the precursor compounds of salbutamol is resolved using a substituted tartaric acid derivative. Specifically, the resolution compound used in US Patent 5,545,745 is selected from (-) - ditholuoyl-L-tartaric acid, (+) - di-toluoyl-D-tartaric acid, (-) - di-benzoyl- L-tartaric acid and (+) - di-benzoyl-D-tartaric acid. Another reference (Hartley et al., Journal of medicinal Chemistry , 1971, Vol. 14, No. 9, pages 895-896) describes almost the same as US Patent 5,545,745: the resolution is carried out with acid (+ ) or (-) di- for -toluoyl tartaric acid. A more recent publication (WO 99/42460) describes the resolution of a new salbutamol ketal derivative (specifically 2- (N-butylamino) -1 - (+ 2,2-dimethyl-1,2-benzodioxin-6-yl) ethanol). Resolution is carried out again with a chiral tartaric acid derivative, such as (+) or (-) di-para-toluyl tartaric acid or (+) or (-) di-O-benzoyl tartaric acid. Salbutamol enantiomers can be produced, if desired, through a complicated multi-stage procedure, which involves the resolution of the ketal derivative. The disadvantage of the procedure described in WO 99/42460 is that the enantiomeric excess of the salts obtained is low (based on the values given in the Examples). This requires additional crystallizations, thus reducing overall yields. In addition, the two additional synthetic stages of ketalization and hydrolysis further reduce the economic viability of the process.

Although the procedure of US 5,545,745 assumes an improvement over previous resolution methods, has, without However, certain disadvantages. Tartaric acid derivatives replaced employees are expensive (and not easily affordable) and they you need to prepare them specially or buy them which adds time and costs to the procedure. These resolution compounds are not they usually recover from the process and this also contributes to higher costs

The authors of the present invention have Found a way to solve these problems. In particular, they have found an effective and economical method of resolving the salbutamol in its optically pure (R) and (S) isomers, a method that does not require the use of substituted tartaric acid derivatives expensive

According to the present invention, a procedure to produce (R) optically pure salbutamol or salts pharmaceutically acceptable thereof, method comprising obtaining isomer (R) of salbutamol or a precursor of salbutamol which is 4-benzyl albuterol or methyl-5- [2 - [(1,1-dimethyl) amino] -1-hydroxyethyl] -2- (phenylmethoxy) -benzoate  in optically pure form by resolution of a racemic mixture or optically impure enantiomers of salbutamol or of said precursor with (L) tartaric acid, and when necessary, convert said isomer of said precursor in salbutamol; later optional conversion of the said (R) optically pure salbutamol into a pharmaceutically acceptable salt.

Unlike the derivatives of tartaric acid used in US Patent 5,545,745, acids (L) and (D) Tartarics are easily affordable and cheap. Can be recovered and reuse in the process if desired, even if not re-use, the procedure is much cheaper than that described in US Patent 5,545,745.

An advantage of the present method is its general applicability to different salbutamol intermediaries. It also allows to obtain a chirally pure product with a good performance.

In an especially preferred aspect of the invention, the compound of salbutamol is used as the compound 4-benzyl albuterol (I) (? - [[(1,1-dimethyl-ethyl) amino] methyl] -4- (phenylmethoxy) -1,3-benzene-dimetanol).  A racemic or optically impure mixture of the compound is resolved to give the (R) and (S) isomers before the Conversion of the desired isomer of salbutamol. He 4-benzyl albuterol is easily available commercially, for example from Cipla Limited.

The precursor 4-benzyl albuterol it is typically prepared, for example, from the ester intermediary methyl-5- [2 - [(1,1-dimethylethyl) amino] -1-hydroxyethyl] -2- (phenylmethoxy) -benzoate (II)

one

This compound (II) can also, if desired, serve as a "precursor of salbutamol" and he resolves himself in its isomers (R) and (S).

The authors of the present invention have found that this resolution method can be used successfully to solve racemic salbutamol itself (or an optically impure mixture of salbutamol enantiomers).

According to this, in another aspect, the invention provides a procedure to produce (R) salbutamol optically pure or pharmaceutically acceptable salts thereof, procedure comprising resolving racemic salbutamol, or a optically impure mixture of salbutamol enantiomers, with acid (L) tartaric, and optional conversion of said (R) salbutamol optically pure in a pharmaceutically acceptable salt of same.

The present invention provides, according to this, several ways to produce (R) salbutamol: by resolution in the final stage, for example on racemic salbutamol, or by resolution to an intermediate stage - for example, by resolution of intermediary alcohol 4-benzyl albuterol or by resolution of the ester intermediary (II), methyl-5- [2 - [(1,1-dimethylethyl) amino] -1-hydroxyethyl] -2- (phenylmethoxy) -benzoate.

The authors of the invention put into practice the procedure using (L) tartaric acid, since this results to the most active isomer (R) salbutamol. However, you can get the production of (S) salbutamol when acid is used (D) tartaric at the resolution stage.

By the term "optically pure", the authors understand an enantiomeric excess (e.e.) (which is a measure well known in the art) of about 95% or more. The term "optically impure" refers to mixtures of enantiomers where the value e.e. is below about 95%, but where the Mix is not exactly racemic. The authors of this invention have found that the resolution step with acid (L) or (D) tartaric is very effective, generally giving a value of e.e. from 99% or more for the chosen isomer.

The implementation of the procedure using the preferred precursor 4-benzyl albuterol, is carried preferably carried out according to the following Scheme A:

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Scheme TO

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In step (a), a suspension of Racemic 4-benzyl albuterol with a solution of (L) tartaric acid in an organic solvent. The authors of the present invention prefer to use a solvent such as methanol, isopropanol, acetone or ethyl acetate or a mixture of two or more of them. The mixture is then cooled to give crystals of salt (L) 4-benzyl albuterol tartrate, which is Then separate and purify. Tartrate salt yield selected is usually more than 30%, with a value of e.e. of about 99%.

In step (b) the optically pure monomer of (R) 4-benzyl albuterol is obtained from a (typically aqueous) solution of the corresponding tartrate salt. The authors prefer to release the free base, from the tartrate salt, by gradual addition of alkali to the salt solution, for example, using sodium hydroxide or sodium carbonate. Can be used also other bases such as hydroxide of which potassium, potassium carbonate, aqueous ammonia and bicarbonate of sodium or potassium Agitation is usually necessary prolonged alkali / salt mixture to precipitate completely the free base from the solution. The yield of the (R) isomer of 4-benzyl albuterol is usually 40% or more over the amount of racemic starting material. The value e.e. stay high, typically 99% or more.

In step (c) the free base (R) 4-benzyl albuterol is de-benzylated in order to give (R) salbutamol. This takes place preferably suspending the 4-benzyl isomer albuterol in an organic solvent such as ethanol, adding a palladium on carbon catalyst and dehydrogenating the suspension under pressure in a hydrogenator. The isomer is then filtered optically pure resulting from salbutamol. If desired, you can obtain a pharmaceutically acceptable salt of the free base by addition of acid (for example dilute sulfuric or hydrochloric acid) of the usual way (see step (d)).

Alternatively, it can be carried out, if you want, the resolution stage earlier in the procedure, by example by resolution of the intermediary ester (II). Acid Tartaric (L) or (D) can be used for resolution, although according to the invention (L) tartaric acid is used to give the form (R) of the ester. This preferred route is the one shown in the Scheme B.

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Scheme B

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The reduction of the isomer (R) of the ester to (R) 4-benzyl albuterol can be carried out, by example, using lithium aluminum hydride, although you can Use any reducing agent. The resolution is carried out typically in the same way as described for 4-benzyl albuterol.

Other salbutamol precursors that may be useful in the process of the invention include derivatives of 4-benzyl albuterol in which the group ring Benzyl is variously substituted. The benzyl group, for example, it may be substituted with one or more halogen atoms (such as chlorine, fluorine or bromine) or one or more alkoxy groups such as methoxy. Other similar substitutions can also be used with the purpose of protecting the phenolic group from the precursor salbutamol, what which will be clear to those skilled in the art.

The following examples are to be understood as Illustrative of the present invention:

Example 1 Preparation of L-Tartrate R-4-Benzyl Albuterol

4-benzyl albuterol is suspended racemic (100 g, 0.30 mol) in methanol (500 ml) and heated to Reflux. It is introduced over approximately 15 minutes a L-tartaric acid solution (50 g, 0.33 mol) in methanol (150 ml). The clear solution is then cooled between 0 and 5 ° C and the crystals are filtered. The wet crystals are collected in isopropanol (300 ml) and heated to reflux, cooled to room temperature and filtered to obtain the compound of title as a white solid (65 g, 45% yield, 99% of e.e.)

Example 2 Preparation of R (-) - 4-benzyl albuterol

The product of Example 1 (65 g, 0.13 mol) is dissolved in water (650 ml) and filtered on celite to separate the insoluble substances The clear filtrate is cooled to 10 ° C and 10% sodium hydroxide solution is slowly added (80 ml) The precipitated sticky solid is free when stirred for 4 hours The solid is filtered, washed with water and dried to obtain the title compound as a solid white (40 g, 40% yield based on the amount of compound racemic, 99% e.e.).

Example 3 Preparation of R (-) Salbutamol Sulfate

It is suspended R-4-benzyl albuterol (40 g, 0.12 moles) in 500 ml of ethanol, 5% palladium on carbon is added (2 g) and shake in a 1 liter Parr hydrogenator at 30 psi (1.42 grams per m2) for 2 hours. The catalyst is filtered and cool the clear filtrate at 15 ° C under stirring. It adds sulfuric acid (4.9 grams, 0.05 moles) drop by drop and the mixture The resulting is stirred for 1 hour and filtered. The solids are washed with ethanol (20 ml) and dried between 45 and 50 ° C in a vacuum oven to give pure R-salbutamol sulfate (30 g, 86% yield).

Example 4 Preparation of R (-) methyl-5- [2 - [(1,1-dimethylethyl) amino] -1-hydroxyethyl] -2- (phenyl-methoxy) -benzoate

Racemic ester is suspended (100 grams, 0.28 moles) in methanol (600 ml) and heated to reflux. One is added L-tartaric acid solution (50 grams, 0.33 moles) in methanol (150 ml) over approximately 30 minutes. The clear solution is then cooled between 0 and 5 ° C and is They filter the crystals. The wet crystals are collected in ethanol (400 ml) and heated to reflux, cooled to room temperature and filter to get the R (-) - ester-L-tartrate As white solid. This is then dissolved in water (500 ml) and Filter on celite to separate insoluble substances. He transparent filtrate is then cooled between 0 and 5 ° C and added an aqueous solution of ammonia to obtain a pH of 8.5 to 9. The mass is then stirred for 3 hours and the solids are filtered, it is wash with water and dry to obtain the title compound (38 grams; 38% yield based on racemic compound, 99% e.e.)

Example 5 Preparation of R (-) - 4-benzyl Albuterol using the R (-) ester of Example 4

The R (-) ester (35.8 g, 0.1 mol) is suspended in Dry tetrahydrofuran (250 ml) and cooled to 0-5 ° C. It adds slowly lithium aluminum hydride (4 grams; 0.33 mol) and the Reaction mass is then stirred for 3 hours. Is introduced then 15% sodium sulfate (20 ml) and the precipitate is separated by filtration The clear filtrate is then concentrated, it is Collect in ethyl acetate (100 ml), cool to 5 ° C and filter to obtain the title compound (30 g; 91%; 99% e.e.).

Example 6

Salbutamol (100 g; 0.41 mol) is dissolved in a 1: 1 mixture of ethyl acetate and methanol (500 ml) at approximately 70 ° C To this solution is added L (+) tartaric acid (66 g; 0.44 moles) under agitation. The contents are maintained at 70 ° C for 2 hours. On cooling, the tartrate salt crystallizes. This is filtered and recrystallize in ethanol to give 52 grams of the tartrate of R (-) pure salbutamol. The salt is then suspended in methanol (200 ml) and a solution of sodium methoxide (15 g; 0.27 mol) is added in methanol The precipitated solids are filtered and the filtrate is cooled at 10 ° C. Sulfuric acid is added slowly to obtain a pH of the reaction mass between 4 and 4.5. The solids are filtered and dried to obtain R (-) salbutamol sulfate (30 grams).

Claims (5)

1. A procedure to produce (R) salbutamol optically pure or pharmaceutically acceptable salts thereof, process comprising obtaining the (R) isomer of salbutamol or a precursor of salbutamol that is 4-benzyl albuterol or methyl-5- [2 - [(1,1-dimethylethyl) amino] -1-hydroxyethyl] -2- (phenylmethoxy) -benzoate in optically pure form by resolution of a racemic mixture or optically impure enantiomers of salbutamol or of said precursor with (L) tartaric acid, and, when necessary, conversion of said isomer of said precursor into salbutamol; optionally, subsequent conversion of said (R) salbutamol optically pure in a pharmaceutically acceptable salt. 2. A method according to claim 1 where the resolution is carried out on racemic salbutamol or on optically impure mixture of salbutamol enantiomers. 3. A method according to claim 1 where the resolution is carried out using racemic mixing or optically impure 4-benzyl enantiomers albuterol or methyl-5- [2 - [(1,1-dimethylethyl) amino] -1-hydroxyethyl] -2- (phenylmethoxy) -benzoate. 4. A procedure according to any of the claims 1 to 3 wherein the optical purity of said isomer precursor of salbutamol and / or the optical purity of the corresponding Salbutamol isomer has an enantiomeric excess value of 95% or more. 5. A method according to claim 4 where the optical purity has a value of 99% or more of excess enantiomeric